Ornithine decarboxylase (ODC) is under cell cycle control and increased ODC activity has been linked to both neoplasm and viral infection. ODC is an effective pharmacological target for the treatment of infections by Trypanosoma brucei. Remarkably, the mechanism of catalysis by ODC has not been clearly demonstrated nor is a structure known. The specific aims of the proposed experiments are: (I) The mechanism of catalysis by ODC will be established as follows: (I.A) Mutagenesis will be utilized to stabilize or destabilize catalytic intermediates. (I.B) The reaction of orn with wild-type and mutant ODC's will be characterized using both CD and UV-visible stopped-flow spectroscopy. (I.C) The pH profile of mutant ODC's will be determined using both steady-state and stopped-flow techniques to correlate the rate constants for formation of individual chemical species with the chemistry of catalysis. (I.D) Solvent isotope effects will be used to help establish the mechanism of catalysis. (II) Two classes of mechanism-based ODC inhibitors will be synthesized and tested, (II.A) Bisubstrate analogs and (II.B) two potential suicide inhibitors.